tbuckley/cabot-search huggingface dataset:
Erythrocyte ENT1-AMPD3 Axis is an Essential Purinergic Hypoxia Sensor and Energy Regulator Combating CKD in a Mouse Model
Authors: Changhan Chen, TingTing Xie, Yujin Zhang, Yiyan Wang, Fang Yu, Lizhen Lin, Weiru Zhang, Benjamin C. Brown, Xin Zhang, Rodney E. Kellems, Angelo D'Alessandro, Yang Xia
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Hypoxia drives kidney damage and progression of CKD. Although erythrocytes respond rapidly to hypoxia, their role and the specific molecules sensing and responding to hypoxia in CKD remain unclear. In this study, we demonstrated in a mouse model that erythrocyte ENT1-AMPD3 is a master energy regulator of the intracellular purinergic hypoxic compensatory response that promotes rapid energy supply from extracellular adenosine, eAMPK-dependent metabolic reprogramming, and O 2 delivery, which combat renal hypoxia and progression of CKD. ENT1-AMPD3-AMPK-BPGM comprise a group of circulating erythroid-specific biomarkers, providing early diagnostic and novel therapeutic targets for CKD. Background Hypoxia drives kidney damage and progression of CKD. Although erythrocytes respond rapidly to hypoxia, their role and the specific molecules sensing and responding to hypoxia in CKD remain unclear. Methods Mice with an erythrocyte-specific deficiency in equilibrative nucleoside transporter 1 ( eEnt1 −/− ) and a global deficiency in AMP deaminase 3 ( Ampd3 −/− ) were generated to define their function in two independent CKD models, including angiotensin II (Ang II) infusion and unilateral ureteral obstruction (UUO). Unbiased metabolomics, isotopic adenosine flux, and various biochemical and cell culture analyses coupled with genetic studies were performed. Translational studies in patients with CKD and cultured human erythrocytes examined the role of ENT1 and AMPD3 in erythrocyte function and metabolism. Results eEnt1 −/− mice display severe renal hypoxia, kidney damage, and fibrosis in both CKD models. The loss of eENT1-mediated adenosine uptake reduces intracellular AMP and thus abolishes the activation of AMPK α and bisphosphoglycerate mutase (BPGM). This results in reduced 2,3-bisphosphoglycerate and glutathione, leading to overwhelming oxidative stress in eEnt1 −/− mice. Excess reactive oxygen species (ROS) activates AMPD3, resulting in metabolic reprogramming and reduced O 2 delivery, leading to severe renal hypoxia in eEnt1 −/− mice. By contrast, genetic ablation of AMPD3 preserves the erythrocyte adenine nucleotide pool, inducing AMPK-BPGM activation, O 2 delivery, and antioxidative stress capacity, which protect against Ang II-induced renal hypoxia, damage, and CKD progression. Translational studies recapitulated the findings in mice. Conclusion eENT1-AMPD3, two highly enriched erythrocyte purinergic components that sense hypoxia, promote eAMPK-BPGM–dependent metabolic reprogramming, O 2 delivery, energy supply, and antioxidative stress capacity, which mitigates renal hypoxia and CKD progression.
Survival with chronic myeloid leukaemia after failing milestones
Authors: Michael Lauseker, Rüdiger Hehlmann, Andreas Hochhaus, Susanne Saußele
Journal: Leukemia (2023)

Abstract Therapy after failing response milestones in CML is controversial. Risks associated with comorbidities, drug toxicities or transplantation may preclude switching to another tyrosine kinase inhibitor (TKI) or other treatments. No information on long-term survival of failing patients is available. To systematically analyse survival after reaching, or not reaching, response milestones, 1342 patients from CML-study IV with newly diagnosed CML in chronic phase and regular molecular tests were studied. Landmark survival analyses were done by &lt;0.1%, 0.1–1%, &gt;1–10% and &gt;10% BCR::ABL1 IS at 3, 6, 12 and 24 months up to 14 years. 10- to 12-year survival of patients who failed the failure milestones (&gt;10% BCR::ABL1 IS at 6 months, &gt;1% BCR::ABL1 IS at 12 months) ranged around 80%, 10% less than in responding patients. These results suggest revision of milestones. Age (more or less than 60 years) had no major impact on survival differences, but on hazard ratios and CML-specific survival. Switching to alternative therapies, which was observed in 26.9% of the patients, did not change the main results. The data show that TKI-treated patients not reaching failure milestones still may derive benefit from continuing TKI-treatment and provide a basis for individualised decisions, if failing patients are confronted with risks of alternative treatments.
National Institutes of Health Funding Gaps for Principal Investigators
Authors: Kelly M. Gillen, Daniel M. Markowitz, Patricia Long, Adriel Villegas-Estrada, Eileen Chang, Ajay Gupta
Journal: JAMA Network Open (2023)

Importance Early-stage and established investigators compete for a limited supply of funds from the National Institutes of Health (NIH). Regardless of their previous funding success, many principal investigators (PIs) encounter a funding gap in which they no longer receive ongoing funding from the NIH. Objective To determine incidence rates of PI-level funding gaps, the mean funding gap length, and whether these 2 metrics are associated with previous funding success. Design, Setting, and Participants This study was conducted using data from NIH RePORTER. Historical datafiles for fiscal year (FY) 2011 to FY 2021 were aggregated to generate 2 master datafiles for this period: all NIH awards and only R01 awards. PIs with no funding in FY 2011 or FY 2021 were removed. PIs were sorted by FY 2011 total funding amounts and grouped by quarter of amount. Results A total of 39 944 unique researchers were awarded 220 131 NIH awards, of which 103 753 were R01 awards. For all NIH awards, there was an overall linear increase from top quarter to bottom quarter in the percentage of PIs who had at least 1 year without funding (from 27% to 75%), percentage of these gap PIs who had at least 2 consecutive years without funding (from 56% to 68%), and mean maximum consecutive years without funding for gap PIs (2.2 years to 3.1 years). For only R01 awards, there was an overall linear increase from top quarter to bottom quarter in the percentage of PIs who had at least 1 year without funding (50% to 74%), percentage of gap PIs who had at least 2 consecutive years without funding (59% to 71%), and mean maximum consecutive years without funding for gap PIs (2.4 years to 3.1 years). Conclusions and Relevance In this cohort study of NIH-funded investigators, PIs with higher NIH funding were less likely to experience a funding gap. Additionally, when these PIs encountered a funding gap, this period without funding was shorter; however, among all PIs, funding gaps typically lasted 2 to 3 years. These associations were found inclusive of all NIH awards and when analysis was limited to only R01 awards. These findings may be useful to PIs and academic institutions as they prepare, structure, and project research resource allocations.
Unravelling Surface Modification Strategies for Preventing Medical Device‐Induced Thrombosis
Authors: Cuong Hung Luu, Nam‐Trung Nguyen, Hang Thu Ta
Journal: Advanced Healthcare Materials (2023)

The use of biomaterials in implanted medical devices remains hampered by platelet adhesion and blood coagulation. Thrombus formation is a prevalent cause of failure of these blood-contacting devices. Although systemic anticoagulant can be used to support materials and devices with poor blood compatibility, its negative effects such as an increased chance of bleeding, make materials with superior hemocompatibility extremely attractive, especially for long-term applications. This review examines blood-surface interactions, the pathogenesis of clotting on blood-contacting medical devices, popular surface modification techniques, mechanisms of action of anticoagulant coatings, and discusses future directions in biomaterial research for preventing thrombosis. In addition, this paper comprehensively reviews several novel methods that either entirely prevent interaction between material surfaces and blood components or regulate the reaction of the coagulation cascade, thrombocytes, and leukocytes.
Correction: Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label randomised controlled ORAL Surveillance trial
Journal: Annals of the Rheumatic Diseases (2023)

In Table 3, there was a typographical error in the upper confidence interval of the hazard ratio for 'history of extra-articular disease: yes versus no' as a risk factor for serious infection events with tofacitinib 5 mg two times per day.The incorrect value was 1.19, this has now been corrected to 1.91.
Author Correction: Multiparameter prediction of myeloid neoplasia risk
Authors: Muxin Gu, Sruthi Cheloor Kovilakam, William G. Dunn, Ludovica Marando, Clea Barcena, Irina Mohorianu, Alexandra Smith, Siddhartha P. Kar, Margarete A. Fabre, Moritz Gerstung, Catherine A. Cargo, Luca Malcovati, Pedro M. Quiros, George S. Vassiliou
Journal: Nature Genetics (2023)
Early Identification of Individuals at Risk for Hypertensive Disorders of Pregnancy
Authors: Janelle Santos, Mauro H. Schenone, Vesna D. Garovic
Journal: JAMA Network Open (2023)

US Preventive Services Task Force; Michael J. Barry, MD; Wanda K. Nicholson, MD, MPH, MBA; Michael Silverstein, MD, MPH; Michael D. Cabana, MD, MA, MPH; David Chelmow, MD; Tumaini Rucker Coker, MD, MBA; Esa M. Davis, MD, MPH; Katrina E. Donahue, MD, MPH; Carlos Roberto Jaén, MD, PhD, MS; Li Li, MD, PhD, MPH; Gbenga Ogedegbe, MD, MPH; Goutham Rao, MD; John M. Ruiz, PhD; James Stevermer, MD, MSPH; Joel Tsevat, MD, MPH; Sandra Millon Underwood, PhD, RN; John B. Wong, MD
Tumor-derived biomarkers predict efficacy of B7H3 antibody-drug conjugate treatment in metastatic prostate cancer models
Authors: Supreet Agarwal, Lei Fang, Kerry McGowen, JuanJuan Yin, Joel Bowman, Anson T. Ku, Aian Neil Alilin, Eva Corey, Martine P. Roudier, Lawrence D. True, Ruth Dumpit, Ilsa Coleman, John K. Lee, Peter S. Nelson, Brian J. Capaldo, Aida Mariani, Clare Hoover, Ilya S. Senatorov, Michael Beshiri, Adam G. Sowalsky, Elaine M. Hurt, Kathleen Kelly
Journal: Journal of Clinical Investigation (2023)

Antibody-drug conjugates(ADCs) are promising targeted cancer therapy; however, patient selection based solely on target antigen expression without consideration for cytotoxic payload vulnerabilities has plateaued clinical benefits. Biomarkers to capture patients who might benefit from specific ADCs have not been systematically determined for any cancer. We present a comprehensive therapeutic and biomarker analysis of a B7H3-ADC with pyrrolobenzodiazepine(PBD) payload in 26 treatment-resistant, metastatic prostate cancer(mPC) models. B7H3 is a tumor-specific surface protein widely expressed in mPC, and PBD is a DNA cross-linking agent. B7H3 expression was necessary but not sufficient for B7H3-PBD-ADC responsiveness. RB1 deficiency and/or replication stress, characteristics of poor prognosis, conferred sensitivity and were associated with complete tumor regression in both neuroendocrine (NEPC) and androgen receptor positive(ARPC) prostate cancer models, even with low B7H3 levels. Non-ARPC models, which are currently lacking efficacious treatment, demonstrated the highest replication stress and were most sensitive to treatment. In RB1 wild-type ARPC tumors, SLFN11 expression or select DNA repair mutations in SLFN11 non-expressors governed response. Importantly, wild-type TP53 predicted non-responsiveness (7/8 models). Overall, biomarker-focused selection of models led to high efficacy of in vivo treatment. These data enable a paradigm shift to biomarker-driven trial designs for maximizing clinical benefit of ADC therapies.
Exercise Training Reduces the Inflammatory Response and Promotes Intestinal Mucosa-Associated Immunity in Lynch Syndrome
Authors: Nan Deng, Laura Reyes-Uribe, Johannes F. Fahrmann, Whittney S. Thoman, Mark F. Munsell, Jennifer B. Dennison, Eunice Murage, Ranran Wu, Ernest T. Hawk, Selvi Thirumurthi, Patrick M. Lynch, Christina M. Dieli-Conwright, Alexander J. Lazar, Sonali Jindal, Khoi Chu, Manoj Chelvanambi, Karen Basen-Engquist, Yisheng Li, Jennifer A. Wargo, Florencia McAllister, James P. Allison, Padmanee Sharma, Krishna M. Sinha, Samir Hanash, Susan C. Gilchrist, Eduardo Vilar
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Lynch syndrome (LS) is a hereditary condition with a high lifetime risk of colorectal and endometrial cancers. Exercise is a non-pharmacologic intervention to reduce cancer risk, though its impact on patients with LS has not been prospectively studied. Here, we evaluated the impact of a 12-month aerobic exercise cycling intervention in the biology of the immune system in LS carriers. Patients and Methods: To address this, we enrolled 21 patients with LS onto a non-randomized, sequential intervention assignation, clinical trial to assess the effect of a 12-month exercise program that included cycling classes 3 times weekly for 45 minutes versus usual care with a one-time exercise counseling session as control. We analyzed the effects of exercise on cardiorespiratory fitness, circulating, and colorectal-tissue biomarkers using metabolomics, gene expression by bulk mRNA sequencing, and spatial transcriptomics by NanoString GeoMx. Results: We observed a significant increase in oxygen consumption (VO2peak) as a primary outcome of the exercise and a decrease in inflammatory markers (prostaglandin E) in colon and blood as the secondary outcomes in the exercise versus usual care group. Gene expression profiling and spatial transcriptomics on available colon biopsies revealed an increase in the colonic mucosa levels of natural killer and CD8+ T cells in the exercise group that were further confirmed by IHC studies. Conclusions: Together these data have important implications for cancer interception in LS, and document for the first-time biological effects of exercise in the immune system of a target organ in patients at-risk for cancer.
Prevalence of mental disorders among Norwegian college and university students: a population-based cross-sectional analysis
Authors: Børge Sivertsen, Ann Kristin Skrindo Knudsen, Benedicte Kirkøen, Jens C. Skogen, Bengt Oscar Lagerstrøm, Kari-Jussie Lønning, Ronald C. Kessler, Anne Reneflot
Journal: The Lancet Regional Health - Europe (2023)

Self-report data indicate a sharp increase in mental health problems among college and university students in recent years, but accurate prevalence estimates of mental disorders are lacking. The current study used a validated psychiatric diagnostic survey, developed into a self-administered electronic version, to examine the prevalence of common mental disorders in a large national sample of college and university students in Norway.Participants (aged 18-35 years) from the national Students' Health and Wellbeing (SHOT) Study in 2022 were recruited to a follow-up online survey of mental disorders from January to February 2023 (n = 10,460). Current (30-days), 12-months and lifetime prevalence of common mental disorders were examined using a newly developed self-administered electronic version of the Composite International Diagnostic Interview (CIDI 5.0).The prevalence of a current mental disorder was high for both women (39.7% [2737/6886], 95% CI 38.6-40.9) and men (25.7% [751/2918], 95% CI 24.2-27.4). The most common disorders were major depressive episode (females 17.1% [1250/7329] and males 10.8% [331/3059]) and generalized anxiety disorder (females 16.0% [1157/7221] and males 8.2% [250/3032]), while 5.6% [387/6948] and 7.7% [228/2963] of the females and male students, respectively, fulfilled the criteria for an alcohol use disorder. The prevalence estimates for 12-month and lifetime were, as expected, even higher.The findings suggest an alarmingly high prevalence of several mental disorders among Norwegian college and university students. Implications and potential methodological and contextual explanations of these findings are discussed.Norwegian Ministry of Education and Research.
Essential role of the Pax5 C-terminal domain in controlling B cell commitment and development
Authors: Sarah Gruenbacher, Markus Jaritz, Louisa Hill, Markus Schäfer, Meinrad Busslinger
Journal: The Journal of Experimental Medicine (2023)

The B cell regulator Pax5 consists of multiple domains whose function we analyzed in vivo by deletion in Pax5. While B lymphopoiesis was minimally affected in mice with homozygous deletion of the octapeptide or partial homeodomain, both sequences were required for optimal B cell development. Deletion of the C-terminal regulatory domain 1 (CRD1) interfered with B cell development, while elimination of CRD2 modestly affected B-lymphopoiesis. Deletion of CRD1 and CRD2 arrested B cell development at an uncommitted pro-B cell stage. Most Pax5-regulated genes required CRD1 or both CRD1 and CRD2 for their activation or repression as these domains induced or eliminated open chromatin at Pax5-activated or Pax5-repressed genes, respectively. Co-immunoprecipitation experiments demonstrated that the activating function of CRD1 is mediated through interaction with the chromatin-remodeling BAF, H3K4-methylating Set1A-COMPASS, and H4K16-acetylating NSL complexes, while its repressing function depends on recruitment of the Sin3-HDAC and MiDAC complexes. These data provide novel molecular insight into how different Pax5 domains regulate gene expression to promote B cell commitment and development.
ALT Flap Single-Stage Donor Site Closure with Loco-Regional Flaps: A Systematic Review
Authors: Glenda Giorgia Caputo, Alessandro Tel, Anna Scarabosio, Filippo Contessi Negrini, Glenda Giorgia Caputo, Marco Gratteri, Mario Alessandri-Bonetti, Pier Camillo Parodi, Roberta Albanese, Sebastiano Mura
Journal: International Journal of Surgery (2023)

The anterolateral thigh (ALT) flap is currently the main choice as a free flap for head and neck reconstruction, including intraoral and facial defects and it is gaining popularity in abdominal, orthopedic and pelvis reconstruction [1]. It can also be used as a pedicled flap in abdominal or perineum reconstruction. One of the most important property of the ALT flap is the low donor site morbidity, both functionally and aesthetically, compared to other workhorse flaps, thanks to the possibility to reach a direct suture in 80% of the cases. Many possibilities are currently available to cover the defect when direct suture is not achievable. A split thickness skin graft has traditionally been used to address the remaining skin defect. Due to the alteration of the thigh skin sensitivity and poor aesthetic outcomes, loco-regional flaps are gaining tremendous momentum in the field. In fact, they allow surgeons to get the donor site closure in one stage surgery, with a good tissue quality, with a like-with-like tissue. A systematic review according to the PRISMA guidelines was performed concerning the issue of donor site closure after ALT harvesting.
Ranitidine Use and Incident Cancer in a Multinational Cohort
Authors: Seng Chan You, Seung In Seo, Thomas Falconer, Chen Yanover, Talita Duarte-Salles, Sarah Seager, Jose D. Posada, Nigam H. Shah, Phung-Anh Nguyen, Yeesuk Kim, Jason C. Hsu, Mui Van Zandt, Min-Huei Hsu, Hang Lak Lee, Heejoo Ko, Woon Geon Shin, Nicole Pratt, Rae Woong Park, Christin G. Reich, Marc A. Suchard, George Hripcsak, Chan Hyuk Park, Daniel Prieto-Alhambra
Journal: JAMA Network Open (2023)

Importance Ranitidine, the most widely used histamine-2 receptor antagonist (H 2 RA), was withdrawn because of N-nitrosodimethylamine impurity in 2020. Given the worldwide exposure to this drug, the potential risk of cancer development associated with the intake of known carcinogens is an important epidemiological concern. Objective To examine the comparative risk of cancer associated with the use of ranitidine vs other H 2 RAs. Design, Setting, and Participants This new-user active comparator international network cohort study was conducted using 3 health claims and 9 electronic health record databases from the US, the United Kingdom, Germany, Spain, France, South Korea, and Taiwan. Large-scale propensity score (PS) matching was used to minimize confounding of the observed covariates with negative control outcomes. Empirical calibration was performed to account for unobserved confounding. All databases were mapped to a common data model. Database-specific estimates were combined using random-effects meta-analysis. Participants included individuals aged at least 20 years with no history of cancer who used H 2 RAs for more than 30 days from January 1986 to December 2020, with a 1-year washout period. Data were analyzed from April to September 2021. Exposure The main exposure was use of ranitidine vs other H 2 RAs (famotidine, lafutidine, nizatidine, and roxatidine). Main Outcomes and Measures The primary outcome was incidence of any cancer, except nonmelanoma skin cancer. Secondary outcomes included all cancer except thyroid cancer, 16 cancer subtypes, and all-cause mortality. Results Among 1 183 999 individuals in 11 databases, 909 168 individuals (mean age, 56.1 years; 507 316 [55.8%] women) were identified as new users of ranitidine, and 274 831 individuals (mean age, 58.0 years; 145 935 [53.1%] women) were identified as new users of other H 2 RAs. Crude incidence rates of cancer were 14.30 events per 1000 person-years (PYs) in ranitidine users and 15.03 events per 1000 PYs among other H 2 RA users. After PS matching, cancer risk was similar in ranitidine compared with other H 2 RA users (incidence, 15.92 events per 1000 PYs vs 15.65 events per 1000 PYs; calibrated meta-analytic hazard ratio, 1.04; 95% CI, 0.97-1.12). No significant associations were found between ranitidine use and any secondary outcomes after calibration. Conclusions and Relevance In this cohort study, ranitidine use was not associated with an increased risk of cancer compared with the use of other H 2 RAs. Further research is needed on the long-term association of ranitidine with cancer development.